Fibulins are a seven-member family of secreted glycoproteins characterized by possessing repeated epidermal growth-factor-like domains and a unique C-terminal structure. Studies of fibulin protein function in cancer indicate that some fibulin proteins have tumor-suppressor activity and some have oncogenic activity. Moreover, some individual fibulin proteins (e.g., fibulin 3/EFEMP1) demonstrate tumor suppressor activity or oncogenic activity in a tissue-specific manner.
EFEMP1 tumor suppressor function is indicated by the following. EFEMP1 has an anti-angiogenic function via suppression of endothelial cell sprouting. EFEMP1 overexpression inhibits tumorigenicity of fibrosarcoma cells. Reduced EFEMP1 expression and/or EFEMP1 promoter methylation occurs in lung, liver, breast, colon, prostate, and nasopharyngeal carcinoma. EFEMP1 expression in glioblastoma multiforme, hepatocellular, and nasopharyngeal carcinoma is correlated with a favorable prognosis. EFEMP1 suppresses AKT signaling activity in nasopharyngeal carcinoma and glioblastoma cell lines
EFEMP1 oncogenic function is indicated by the following. Elevated EFEMP1 expression has been correlated to poor prognosis for cervical cancer. The results of a clinical trial demonstrated that EFEMP1 over-expression was correlated to poor prognosis for breast carcinoma. In pancreatic adenocarcinoma cells, EFEMP1 over-expression promotes xenograft formation. EFEMP1 activates AKT signaling activity in pancreatic carcinoma cell lines. In certain glioma cells, EFEMP1 has been shown to enhance in vitro substrate-specific cell adhesion and promote cell motility and dispersion.
The deadly form of brain cancer, glioblastoma multiforme (GBM), for which there is not yet any effective treatment, is made up of disparate subpopulations of cells characterized by having distinct proliferation and infiltration properties. The mechanism underlying GBM recurrence after treatment, such as surgery, radiation, and chemotherapy, has not been conclusively identified. It has been speculated that recurrence is caused by an infiltrative subpopulation of GBM cells that have neural stem cell properties (so-called tumor stem cells) and are resistant to radiation and chemotherapy. GBM growth appears largely dependent on an angiogenic tumor microenvironment, and anti-angiogenic therapies have been shown to temporarily repress GBM tumor growth. But anti-angiogenic therapies do not improve overall survival of GBM patients and result in tumor recurrence with an increased pattern of infiltration. Previously, a therapy targeting glioma cell infiltration has been lacking.